Toll-like receptors: a link between mechanical ventilation, innate immunity and lung injury?

Excerpt

In critically ill patients, the lung is exposed to various aggressors. Mechanical stress resulting from mechanical ventilation (MV), systemic inflammation and bacteria are probably the main insults that the lung has to face. An accumulation of experimental evidence now supports the hypothesis that large tidal volumes (V_T) along with the absence of positive end-expiratory pressure promotes lung injury (i.e. ventilator-induced lung injury) [1]. The clinical relevance of ventilator-induced lung injury has been illustrated by studies showing that MV in the conditions listed above is an independent predictor of death in patients with established lung injury as well as in those at risk of injury [2, 3]. Sepsis, aspiration, haemorrhagic shock, major surgery and trauma are therefore high-risk conditions since they are likely to trigger an inflammatory response in the host. In addition, clinical and experimental findings support the theory that both insults could act synergistically and cause lung inflammation and injury [4]. The underlying mechanisms of the so-called “two-hit” paradigm have been investigated. The lung can be “primed” by mechanical stretch, which drives an increased inflammatory response to a second insult such as exposure to microbial agents or to systemic inflammation [5]. It has been experimentally demonstrated that pulmonary epithelial cells and alveolar macrophages subjected to a combination of cyclic stretch and cytokines such as tumour necrosis factor-α and interleukin-1β or bacterial molecules such as lipopolysaccharide (LPS) release substantially more inflammatory mediators than cells kept static [6‐8]. Interestingly, cell stretch activates similar intracellular signalling pathways (NF-κB, MAPK) as those induced by proinflammatory cytokines [9]. Cooperation and synergism between transcriptional factors is currently thought to be the underlying molecular mechanism that causes the combined effect of the two insults [10]. …